Recent studies have demonstrated that a simple ketone [acetone, (CH3)2C＝O)] reacts with the Si(100) surface in a [2+2] C＝O cycloaddition or by α-H cleavage to form Si-C and/or Si-O σ-bonds. To understand the reactivity of carbonyl compounds bearing different substitutes, the [2 + 2] C＝O cycloaddition and α-H cleavage of carbonyl compounds CH3COR (R=CH3, H, C2H5, C6H5) on Si(100) surface have been investigated using density functional theory at the B3LYP/6-311 ++ G(d,p)//6-31G(d) level. Our calculation results reveal that: (1) both cycloaddition and α-H cleavage corresponds to very low energy barriers (lower than 25 kJ•mol-1), and the energy barrier for cycloaddition is slightly higher than α-H cleavage; (2) the substituents on the carbonyl compound [CH3COR] has only a minor influence on the energy barrier; (3) the α-H cleavage reactions are thermodynamically and kinetically more favorable than cycloadditions; (4) for the α-H cleavage of butanone, reactions at C1 and C3 positions are competitive. These findings suggest that the reactions of ketone derivatives with Si(100) surface will generate multiple products.